Project II: Summary/Abstract Dopamine-resistant gait and postural dysfunctions represent a critical unmet need in Parkinson disease (PD). Evidence is accumulating that cholinergic system dysfunction contributes significantly to gait and balance impairment. The cholinergic system is implicated in mobility functions in PD because of loss of cholinergic basal forebrain (BF) neurons directing attention and degeneration of cholinergic neurons in the pedunculopontine nucleus (PPN) complex. Although mobility functions require intrinsic coupling between locomotor and postural functions, our work points to dissociable and additive motor deficits characterized by specific associations with BF vs. PPN cholinergic degenerations. Our recent work shows that slowing of gait speed appears to be a good correlate of BF cholinergic degeneration in patients with mild to moderate PD. We have also data suggesting that cholinergic thalamic denervation, reflecting PPN cholinergic afferent degeneration, is associated with falls and postural dysfunction in PD. These results implicate PPN degeneration as a significant mechanistic factor contributing to impaired postural control in PD. Progressive mobility impairments likely reflect cumulative effects of multisystem degenerations in PD. The goal of this project is to study the different contributions of cholinergic projection system degenerations to PD gait and postural dysfunctions. Together with the other Projects in this Udall Center proposal, this study will contribute to testing of the ?3-Hit? model of gait and balance dysfunction in PD (detailed in Overview). This model posits that serial degeneration of nigrostriatal (first ?hit?) and BF/PPN cholinergic systems (second and third ?hits?, resp.) are responsible for the typically inexorable progression of dopamine-resistant gait and postural dysfunction in PD. We hypothesize that BF and PPN deficits contribute to dissociable and additive components of PD gait and postural dysfunction. Our center developed a novel vesicular acetylcholine transporter (VAChT) PET ligand, fluoroethoxy-benzovesamicol ([18F]FEOBV), which enables a more accurate assessment of cholinergic nerve terminal integrity compared to previously used cholinesterase-based ligands. Most notably, [18F]FEOBV will allow quantitative assessment of cholinergic terminals in the cerebellar vermis, which originates in the PPN. The spinocerebellum is important in the regulation of postural control through the processing of propioceptive information. Identification of pathway specific deficits may lead to novel therapeutic targets for treatment of gait and balance disorders in PD. This proposal is directly responsive to the NINDS PD 2014 Research Report highest priority recommendations including 1) developing biomarkers for dopa-resistant features of PD, in particular gait and balance problems (Clinical Rec. #2); 2) characterizing mechanisms that underlie the heterogeneity in clinical presentation and rates of PD progression (Clinical Rec. #3); and 3) development of patient stratification tools to define more homogenous cohorts of PD subjects (Translational Rec. #1).